Efficacy and immunogenicity following dengue virus-1 human challenge after a tetravalent prime-boost dengue vaccine regimen: an open-label, phase 1 trial.

BACKGROUND: Dengue human infection models (DHIMs) are important tools to down-select dengue vaccine candidates and establish tetravalent efficacy before advanced clinical field trials. We aimed to provide data for the safety and immunogenicity of DHIM and evaluate dengue vaccine efficacy. METHODS: We performed an open-label, phase 1 trial at the University of Maryland (Baltimore, MD, USA). Eligible participants were healthy individuals aged 18-50 years who either previously received a tetravalent dengue purified inactivated vaccine prime followed by a live-attenuated vaccine boost (ie, the vaccinee group), or were unvaccinated flavivirus-naive participants (ie, the control group). Participants in the vaccinee group with detectable pre-challenge dengue virus-1 neutralising antibody titres and flavivirus-naive participants in the control group were inoculated with dengue virus-1 strain 45AZ5 in the deltoid region, 27-65 months following booster dosing. These participants were followed-up from days 4-16 following dengue virus-1 live virus human challenge, with daily real-time quantitative PCR specific to dengue virus-1 RNA detection, and dengue virus-1 solicited local and systemic adverse events were recorded. The primary outcomes were safety (ie, solicited local and systemic adverse events) and vaccine efficacy (ie, dengue virus-1 RNAaemia) following dengue challenge. This study is registered with ClinicalTrials.gov, number NCT04786457. FINDINGS: In January 2021, ten eligible participants were enrolled; of whom, six (60%) were in the vaccinee group and four (40%) were in the control group. Daily quantitative PCR detected dengue virus-1 RNA in nine (90%) of ten participants (five [83%] of six in the vaccinee group and all four [100%] in the control group). The mean onset of RNAaemia occurred on day 5 (SD 1·0) in the vaccinee group versus day 8 (1·5) in the control group (95% CI 1·1-4·9; p=0·007), with a trend towards reduced RNAaemia duration in the vaccinee group compared with the control group (8·2 days vs 10·5 days; 95% CI -0·08 to 4·68; p=0·056). Mild-to-moderate symptoms (nine [90%] of ten), leukopenia (eight [89%] of nine), and elevated aminotransferases (seven [78%] of nine) were commonly observed. Severe adverse events were detected only in the vaccinee group (fever ≥38·9°C in three [50%] of six, headache in one [17%], and transient grade 4 aspartate aminotransferase elevation in one [17%]). No deaths were reported. INTERPRETATION: Participants who had tetravalent dengue purified inactivated vaccine prime and live-attenuated vaccine boost were unprotected against dengue virus-1 infection and further showed increased clinical, immunological, and transcriptomic evidence for inflammation potentially mediated by pre-existing infection-enhancing antibodies. This study highlights the impact of small cohort, human challenge models studying dengue pathogenesis and downstream vaccine development. FUNDING: Military Infectious Disease Research Program and Medical Technology Enterprise Consortium and Advanced Technology International.

Helicobacter pylori Infection and Complications of Cirrhosis.

INTRODUCTION: Helicobacter pylori is a significant contributor to conditions such as peptic ulcer disease, gastric cancer, gastric mucosa-associated lymphoid tissue lymphoma, and colorectal cancer. Recent studies have suggested a potential link between H. pylori and cirrhosis. However, the impact of H. pylori on cirrhosis-related mortality, inpatient outcomes, and decompensating events remains unclear. Considering the widespread availability of H. pylori testing and effective treatment options, there is a potential rationale for eradicating H. pylori in cirrhotic patients to mitigate the morbidity and mortality associated with cirrhosis. This study aims to investigate the association between H. pylori and inpatient outcomes and complications related to cirrhosis. METHODS: The National Inpatient Sample (NIS) database, a part of the Healthcare Cost & Utilization Project, was utilized for this study. Inpatient data from the years 2016 through 2019 were extracted for patients with a primary discharge diagnosis of cirrhosis and a concurrent diagnosis of H. pylori infection. The primary outcomes included inpatient mortality, length of stay, and cost of care. Secondary outcomes involved cirrhosis-related complications during hospitalization, such as gastrointestinal bleeding, hepatic encephalopathy, and hepatorenal syndrome. RESULTS: Over the years 2016 to 2019, 416,410 patients received a primary discharge diagnosis of cirrhosis. Among them, 990 patients (0.2%) had a secondary diagnosis of H. pylori infection. Those with both cirrhosis and H. pylori tended to be younger on average (mean age 54.25 vs. 57.18 years, p=0.01) and more frequently fell within the age range of 18-49 (33.84% vs. 24.71%, P=0.01). H. pylori-infected patients were also more likely to be male (70.71% vs. 63.11%, P<0.028), of Hispanic race (36.4% vs. 18.6%, p< 0.1), and of Black race (20.2% vs. 8.1%, p< 0.1). While H. pylori-exposed patients had lower in-hospital mortality (0.51% vs. 4.44%, p=0.007), their mean length of stay was higher (6.97 days vs. 5.75, p=0.002). The overall cost of care was comparable between the H. pylori-exposed and non-exposed groups (mean USD18,106.18 vs. $16,543.49, P=0.160). H. pylori-exposed patients had a higher overall rate of cirrhosis-related complications (84.85% vs. 67.59%, p< 0.001), gastrointestinal bleeding (48.48% vs. 27.34%, p< 0.001), and hepatorenal syndrome (70.71% vs. 46.99%, p< 0.001), and these differences persisted in multivariable analysis. Initially, rates of hepatic encephalopathy were higher in H. pylori non-exposed patients (21.57% vs. 15.66%, p=0.04), but this discrepancy was corrected after adjusting for potential confounders. CONCLUSION: While patients in this study were diagnosed with both H. pylori and cirrhosis by discharge, it cannot be definitively concluded that H. pylori was the direct cause of cirrhosis complications. Recognizing this uncertainty, further studies are needed better to understand the associations between cirrhosis and H. pylori complications. Distinguishing the causes of cirrhosis and its relationship with H. pylori may offer deeper insights into whether H. pylori is a causative factor or merely correlated in its effects on patients with cirrhosis.

Recombinant full-length Plasmodium falciparum circumsporozoite protein-based vaccine adjuvanted with GLA-LSQ: Results of Phase 1 testing with malaria challenge.

INTRODUCTION: Malaria is preventable yet causes >600,000 deaths annually. RTS, S, the first marketed malaria vaccine, has modest efficacy, but improvements are needed for eradication. METHODS: We conducted an open-label, dose escalation Phase 1 study of a recombinant, full-length circumsporozoite protein vaccine (rCSP) administered with adjuvant GLA-LSQ on days 1, 29, and 85 or 1 and 490 to healthy, malaria-naïve adults. Primary endpoints were safety and reactogenicity. Secondary endpoints were antibody responses and Plasmodium falciparum parasitemia after homologous controlled human malaria infection (CHMI). RESULTS: Participants were enrolled into four groups receiving rCSP/GLA-LSQ: 10 µg x 3 (n = 20), 30 µg x 3 (n = 10), 60 µg x 3 (n = 10) or 60 µg x 2 (n = 9); ten participants received 30 µg rCSP alone x 3; and six infectivity controls. Participants experienced no serious adverse events. Rates of solicited and unsolicited adverse events were similar among groups. All 26 participants who underwent CHMI 28 days after final vaccinations developed malaria. Increasing vaccine doses induced higher IgG titers, but did not achieve previously established RTS, S benchmarks. CONCLUSIONS: rCSP/GLA-LSQ had favorable safety results. However, tested regimens did not induce protective immunity. Further investigation could assess if adjuvant or schedule adjustments improve efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03589794.

hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50.

The anti-cancer target hRpn13 is a proteasome substrate receptor. However, hRpn13-targeting molecules do not impair its interaction with proteasomes or ubiquitin, suggesting other critical cellular activities. We find that hRpn13 depletion causes correlated proteomic and transcriptomic changes, with pronounced effects in myeloma cells for cytoskeletal and immune response proteins and bone-marrow-specific arginine deiminase PADI4. Moreover, a PROTAC against hRpn13 co-depletes PADI4, histone deacetylase HDAC8, and DNA methyltransferase MGMT. PADI4 binds and citrullinates hRpn13 and proteasomes, and proteasomes from PADI4-inhibited myeloma cells exhibit reduced peptidase activity. When off proteasomes, hRpn13 can bind HDAC8, and this interaction inhibits HDAC8 activity. Further linking hRpn13 to transcription, its loss reduces nuclear factor κB (NF-κB) transcription factor p50, which proteasomes generate by cleaving its precursor protein. NF-κB inhibition depletes hRpn13 interactors PADI4 and HDAC8. Altogether, we find that hRpn13 acts dually in protein degradation and expression and that proteasome constituency and, in turn, regulation varies by cell type.

Can incorporating genotyping data into efficacy estimators improve efficiency of early phase malaria vaccine trials?

BACKGROUND: Early phase malaria vaccine field trials typically measure malaria infection by PCR or thick blood smear microscopy performed on serially sampled blood. Vaccine efficacy (VE) is the proportion reduction in an endpoint due to vaccination and is often calculated as VEHR = 1-hazard ratio or VERR = 1-risk ratio. Genotyping information can distinguish different clones and distinguish multiple infections over time, potentially increasing statistical power. This paper investigates two alternative VE endpoints incorporating genotyping information: VEmolFOI, the vaccine-induced proportion reduction in incidence of new clones acquired over time, and VEC, the vaccine-induced proportion reduction in mean number of infecting clones per exposure. METHODS: Power of VEmolFOI and VEC was compared to that of VEHR and VERR by simulations and analytic derivations, and the four VE methods were applied to three data sets: a Phase 3 trial of RTS,S malaria vaccine in 6912 African infants, a Phase 2 trial of PfSPZ Vaccine in 80 Burkina Faso adults, and a trial comparing Plasmodium vivax incidence in 466 Papua New Guinean children after receiving chloroquine + artemether lumefantrine with or without primaquine (as these VE methods can also quantify effects of other prevention measures). By destroying hibernating liver-stage P. vivax, primaquine reduces subsequent reactivations after treatment completion. RESULTS: In the trial of RTS,S vaccine, a significantly reduced number of clones at first infection was observed, but this was not the case in trials of PfSPZ Vaccine or primaquine, although the PfSPZ trial lacked power to show a reduction. Resampling smaller data sets from the large RTS,S trial to simulate phase 2 trials showed modest power gains from VEC compared to VEHR for data like those from RTS,S, but VEC is less powerful than VEHR for trials in which the number of clones at first infection is not reduced. VEmolFOI was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate VEmolFOI. The primaquine VEmolFOI estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing VEmolFOI from improving power. CONCLUSIONS: The power gain from the genotyping methods depends on the context. Because input parameters for early phase power calculations are often uncertain, these estimators are not recommended as primary endpoints for small trials unless supported by targeted data analysis. TRIAL REGISTRATIONS: NCT00866619, NCT02663700, NCT02143934.

Can incorporating genotyping data into efficacy estimators improve efficiency of early phase malaria vaccine trials?

Background: Early phase malaria vaccine field trials typically measure malaria infection by PCR or thick blood smear microscopy performed on serially sampled blood. Vaccine efficacy (VE) is the proportion reduction in an endpoint due to vaccination and is often calculated as VEHR=1 - hazard ratio or VERR=1 - risk ratio. Genotyping information can distinguish different clones and distinguish multiple infections over time, potentially increasing statistical power. This paper investigates two alternative VE endpoints incorporating genotyping information: VEmolFOI, the vaccine-induced proportion reduction in incidence of new clones acquired over time, and VEC, the vaccine-induced proportion reduction in mean number of infecting clones per exposure. Methods: We used simulations and analytic derivations to compare power of these methods to VEHR and VERR and applied them to three data sets: a Phase 3 trial of RTS,S malaria vaccine in 6912 African infants, a Phase 2 trial of PfSPZ Vaccine in 80 Burkina Faso adults, and a trial comparing Plasmodium vivax incidence in 466 Papua New Guinean children after receiving chloroquine + artemether lumefantrine with or without primaquine (as these VE methods can also quantify effects of other prevention measures). By destroying hibernating liver-stage P. vivax, primaquine reduces subsequent reactivations after treatment completion. Results: The RTS,S vaccine significantly reduced the number of clones at first infection, but PfSPZ vaccine and primaquine did not. Resampling smaller data sets from the large RTS,S trial to simulate phase 2 trials showed modest power gains from VEC compared to VEHR for data like RTS,S, but VEC is less powerful than VEHR for vaccines which do not reduce the number of clones at first infection. VEmolFOI was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate VEmolFOI. The primaquine VEmolFOI estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing VEmolFOI from improving power. Conclusions: The power gain from the genotyping methods depends on the context. Because input parameters for early phase power calculations are often uncertain, we recommend against these estimators as primary endpoints for small trials unless supported by targeted data analysis. Trial registrations: NCT00866619, NCT02663700, NCT02143934.

Ongoing declines for the world's amphibians in the face of emerging threats.

Systematic assessments of species extinction risk at regular intervals are necessary for informing conservation action1,2. Ongoing developments in taxonomy, threatening processes and research further underscore the need for reassessment3,4. Here we report the findings of the second Global Amphibian Assessment, evaluating 8,011 species for the International Union for Conservation of Nature Red List of Threatened Species. We find that amphibians are the most threatened vertebrate class (40.7% of species are globally threatened). The updated Red List Index shows that the status of amphibians is deteriorating globally, particularly for salamanders and in the Neotropics. Disease and habitat loss drove 91% of status deteriorations between 1980 and 2004. Ongoing and projected climate change effects are now of increasing concern, driving 39% of status deteriorations since 2004, followed by habitat loss (37%). Although signs of species recoveries incentivize immediate conservation action, scaled-up investment is urgently needed to reverse the current trends.

Immunogenomic profile at baseline predicts host susceptibility to clinical malaria.

Introduction: Host gene and protein expression impact susceptibility to clinical malaria, but the balance of immune cell populations, cytokines and genes that contributes to protection, remains incompletely understood. Little is known about the determinants of host susceptibility to clinical malaria at a time when acquired immunity is developing. Methods: We analyzed peripheral blood mononuclear cells (PBMCs) collected from children who differed in susceptibility to clinical malaria, all from a small town in Mali. PBMCs were collected from children aged 4-6 years at the start, peak and end of the malaria season. We characterized the immune cell composition and cytokine secretion for a subset of 20 children per timepoint (10 children with no symptomatic malaria age-matched to 10 children with >2 symptomatic malarial illnesses), and gene expression patterns for six children (three per cohort) per timepoint. Results: We observed differences between the two groups of children in the expression of genes related to cell death and inflammation; in particular, inflammatory genes such as CXCL10 and STAT1 and apoptotic genes such as XAF1 were upregulated in susceptible children before the transmission season began. We also noted higher frequency of HLA-DR+ CD4 T cells in protected children during the peak of the malaria season and comparable levels cytokine secretion after stimulation with malaria schizonts across all three time points. Conclusion: This study highlights the importance of baseline immune signatures in determining disease outcome. Our data suggests that differences in apoptotic and inflammatory gene expression patterns can serve as predictive markers of susceptibility to clinical malaria.

Differences in treatment and outcomes among patients with ST-segment elevation myocardial infarction with and without standard modifiable risk factors: a systematic review and meta-analysis.

There are limited data available on outcomes and pathophysiology behind ST-segment elevation myocardial infarction (STEMI) in populations without standard modifiable risk factors (SMuRFs). The authors carried out this meta-analysis to understand the differences in treatment and outcomes of STEMI patients with and without SMuRFs. Methods: A systematic database search was performed for relevant studies. Studies reporting desired outcomes among STEMI patients with and without SMuRFs were selected based on predefined criteria in the study protocol (PROSPERO: CRD42022341389). Two reviewers independently screened titles and abstracts using Covidence. Full texts of the selected studies were independently reviewed to confirm eligibility. Data were extracted from all eligible studies via a full-text review of the primary article for qualitative and quantitative analysis. In-hospital mortality following the first episode of STEMI was the primary outcome, with major adverse cardiovascular events (MACE), repeat myocardial infarction (MI), cardiogenic shock, heart failure, and stroke as secondary outcomes of interest. Odds ratio (OR) with a 95% CI was used to estimate the effect. Results: A total of 2135 studies were identified from database search, six studies with 521 150 patients with the first STEMI episode were included in the analysis. The authors found higher in-hospital mortality (OR: 1.43; CI: 1.40-1.47) and cardiogenic shock (OR: 1.59; 95% CI: 1.55-1.63) in the SMuRF-less group with no differences in MACE, recurrent MI, major bleeding, heart failure, and stroke. There were lower prescriptions of statin (OR: 0.62; CI: 0.42-0.91) and Angiotensin converting enzyme inhibitor /Angiotensin II receptor blocker (OR: 0.49; CI: 0.28-0.87) at discharge in SMuRF-less patients. There was no difference in procedures like coronary artery bypass graft, percutaneous coronary intervention, and thrombolysis. Conclusion: In the SMuRF-less STEMI patients, higher in-hospital mortality and treatment discrepancies were noted at discharge.

Constrictive Pericarditis from an Atraumatic Hemopericardium After Systemic Thrombolysis for a Massive Pulmonary Embolism.

Constrictive pericarditis most commonly results from fibrosis and adhesions of the parietal and visceral pericardium due to long-standing inflammation. Common etiologies include idiopathic, post-surgical, radiation injury and infectious etiologies including tuberculosis. Traumatic hemopericardium is a rare cause of constrictive pericarditis but atraumatic hemopericardium causing constrictive pericarditis has not been reported in the literature to date. We present a case of constrictive pericarditis from an atraumatic hemopericardium after systemic thrombolysis for a massive pulmonary embolism.

Severe Malaria with a Rare Tetrad of Blackwater Fever, Acute Renal Failure, Disseminated Intravascular Coagulopathy, and Acute Acalculous Cholecystitis.

Background: Blackwater fever (BWF) is a severe clinical syndrome occurring as a complication of malarial infection characterized by intravascular hemolysis, hemoglobinuria, and acute renal failure in people exposed to Plasmodium falciparum and, to some extent, in people who were exposed to medications like quinine and mefloquine. The exact pathogenesis of classic BWF remains unclear. The mechanism leading to damage to the red blood cells (RBCs) can be immunologic nonimmunologic, leading to massive intravascular hemolysis. Case Presentation. We present a case of classic blackwater fever in a 24-year-old otherwise previously healthy male without any history of antimalarial prophylaxis use, returning from recent travel to Sierra Leone. He was detected to have P. falciparum malaria in the peripheral smear test. He was treated with artemether/lumefantrine combination therapy. Unfortunately, his presentation was complicated by renal failure and was managed with plasmapheresis and renal replacement therapy. Conclusion: Malaria continues to be a parasitic disease that can have devastating effects and continues to be a challenge globally. Although cases of malaria in the United States are rare and cases of severe malaria, mainly attributed to P. falciparum, are even more uncommon. Care should be taken to retain a high level of suspicion to consider the diagnosis, especially in returning travelers from endemic areas.

Gender Disparities after Transcatheter Aortic Valve Replacement with Newer Generation Transcatheter Heart Valves: A Systematic Review and Meta-Analysis.

Previous studies have demonstrated gender disparities in mortality and vascular complications after transcatheter aortic valve replacement (TAVR) with early generation transcatheter heart valves (THVs). It is unclear, however, whether gender-related differences persist with the newer generation THVs. We aim to assess gender disparities after TAVR with newer generation THVs. The MEDLINE and Embase databases were thoroughly searched from inception to April 2023 to identify studies that reported gender-specific outcomes after TAVR with newer generation THVs (Sapien 3, Corevalve Evolut R, and Evolut Pro). The outcomes of interest included 30-day mortality, 1-year mortality, and vascular complications. In total, 5 studies (4 databases) with a total of 47,933 patients (21,073 females and 26,860 males) were included. Ninety-six percent received TAVR via the transfemoral approach. The females had higher 30-day mortality rates (odds ratio (OR) = 1.53, 95% confidence interval (CI) 1.31-1.79, p-value (p) < 0.001) and vascular complications (OR = 1.43, 95% CI 1.23-1.65, p < 0.001). However, one-year mortality was similar between the two groups (OR = 0.78, 95% CI 0.61-1.00, p = 0.28). The female gender continues to be associated with higher 30-day mortality rates and vascular complications after TAVR with newer generation transcatheter heart valves, while there was no difference in 1-year mortality between the genders. More data is needed to explore the causes and whether we can improve TAVR outcomes in females.

Sex differences in atrial fibrillation ablation in-hospital outcomes from the National Inpatient Sample database 2016-2019.

Background: Research has shown mixed results when comparing in-hospital complications following atrial fibrillation ablation in women compared to men. Objectives: To better quantify sex differences and in-hospital outcomes in atrial fibrillation ablation procedures and identify factors associated with poorer outcomes. Methods: We queried the NIS database from 2016 to 2019 for hospitalizations with a primary diagnosis of atrial fibrillation ablation and excluded patients with any other arrhythmias, ICD/pacemaker placement. We assessed demographics, in-hospital mortality, and complications of women compared to men. Results: Admissions for atrial fibrillation were more common in females than males (849 050 vs. 815 665; p < .001). However, females were less likely to receive ablation (1.65% vs. 2.71%, OR: 0.60; 95% confidence interval: 0.57-0.64, p < .001), which persisted after adjusting for cardiomyopathy (adjusted OR: 0.61; 95% confidence interval: 0.58-0.65, p < .001). The primary outcome of in-hospital mortality was not statistically different in univariate analysis (0.39% vs. 0.36%, OR: 1.09, 95% CI: 0.44-2.72, p = .84), finding that did not change when adjusted for comorbidities (adjusted OR: 0.94, 95% CI: 0.36-2.49). The complication rate in hospitalized patients following ablation was 8.08%. The total unadjusted complication rate was higher for females than males (9.58% vs. 7.09%, p = .001); however, it was not significant when adjusted for risks (adjusted OR: 1.23, 95% CI: 0.99-1.53, p = .06). Conclusion: Female sex is not associated with increased complications or death in a real-world study of catheter ablation when results are adjusted for risks. However, females admitted with atrial fibrillation receive ablation less often than males during hospital admission.

Low-dose intravenous and subcutaneous CIS43LS monoclonal antibody for protection against malaria (VRC 612 Part C): a phase 1, adaptive trial.

BACKGROUND: Human monoclonal antibodies might offer an important new approach to reduce malaria morbidity and mortality. In the first two parts of a three-part clinical trial, the antimalarial monoclonal antibody CIS43LS conferred high protection against parasitaemia at doses of 20 mg/kg or 40 mg/kg administered intravenously followed by controlled human malaria infection. The ability of CIS43LS to confer protection at lower doses or by the subcutaneous route is unknown. We aimed to provide data on the safety and optimisation of dose and route for the human antimalaria monoclonal antibody CIS43LS. METHODS: VRC 612 Part C was the third part of a three-part, first-in-human, phase 1, adaptive trial, conducted at the University of Maryland, Baltimore Center for Vaccine Development and Global Health, Baltimore, MD, USA. We enrolled adults aged 18-50 years with no previous malaria vaccinations or infections, in a sequential, dose-escalating manner. Eligible participants received the monoclonal antibody CIS43LS in a single, open-label dose of 1 mg/kg, 5 mg/kg, or 10 mg/kg intravenously, or 5 mg/kg or 10 mg/kg subcutaneously. Participants underwent controlled human malaria infection by the bites of five mosquitoes infected with Plasmodium falciparum 3D7 strain approximately 8 weeks after their monoclonal antibody inoculation. Six additional control participants who did not receive CIS43LS underwent controlled human malaria infection simultaneously. Participants were followed-up daily on days 7-18 and day 21, with qualitative PCR used for P falciparum detection. Participants who tested positive for P falciparum were treated with atovaquone-proguanil and those who remained negative were treated at day 21. Participants were followed-up until 24 weeks after dosing. The primary outcome was safety and tolerability of CIS43LS at each dose level, assessed in the as-treated population. Secondary outcomes included protective efficacy of CIS43LS after controlled human malaria infection. This trial is now complete and is registered with ClinicalTrials.gov, NCT04206332. FINDINGS: Between Sept 1, 2021, and Oct 29, 2021, 47 people were assessed for eligibility and 31 were enrolled (one subsequently withdrew and was replaced) and assigned to receive doses of 1 mg/kg (n=7), 5 mg/kg (n=4), and 10 mg/kg (n=3) intravenously and 5 mg/kg (n=4) and 10 mg/kg (n=4) subcutaneously, or to the control group (n=8). CIS43LS administration was safe and well tolerated; no serious adverse events occurred. CIS43LS protected 18 (82%) of 22 participants who received a dose. No participants developed parasitaemia following dosing at 5 mg/kg intravenously or subcutaneously, or at 10 mg/kg intravenously or subcutaneously. All six control participants and four of seven participants dosed at 1 mg/kg intravenously developed parasitaemia after controlled human malaria infection. INTERPRETATION: CIS43LS was safe and well tolerated, and conferred protection against P falciparum at low doses and by the subcutaneous route, providing evidence that this approach might be useful to prevent malaria across several clinical use cases. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health.

A randomized controlled trial showing safety and efficacy of a whole sporozoite vaccine against endemic malaria.

A highly effective malaria vaccine remains elusive despite decades of research. Plasmodium falciparum sporozoite vaccine (PfSPZ Vaccine), a metabolically active, nonreplicating, whole parasite vaccine demonstrated safety and vaccine efficacy (VE) against endemic P. falciparum for 6 months in Malian adults receiving a five-dose regimen. Safety, immunogenicity, and VE of a three-dose regimen were assessed in adults in Balonghin, Burkina Faso in a two-component study: an open-label dose escalation trial with 32 participants followed by a double-blind, randomized, placebo-controlled trial (RCT) with 80 participants randomized to receive three doses of 2.7 × 106 PfSPZ (N = 39) or normal saline (N = 41) just before malaria season. To clear parasitemia, artesunate monotherapy was administered before first and last vaccinations. Thick blood smear microscopy was performed on samples collected during illness and every 4 weeks for 72 weeks after last vaccinations, including two 6-month malaria transmission seasons. Safety outcomes were assessed in all 80 participants who received at least one dose and VE for 79 participants who received three vaccinations. Myalgia was the only symptom that differed between groups. VE (1 - risk ratio; primary VE endpoint) was 38% at 6 months (P = 0.017) and 15% at 18 months (0.078). VE (1 - hazard ratio) was 48% and 46% at 6 and 18 months (P = 0.061 and 0.018). Two weeks after the last dose, antibodies to P. falciparum circumsporozoite protein and PfSPZ were higher in protected versus unprotected vaccinees. A three-dose regimen of PfSPZ Vaccine demonstrated safety and efficacy against malaria infection in malaria-experienced adults.

Gene Coverage Count and Classification (GC3): a locus sequence coverage assessment tool using short-read whole genome sequencing data, and its application to identify and classify histidine-rich protein 2 and 3 deletions in Plasmodium falciparum.

BACKGROUND: The ability of malaria rapid diagnostic tests (RDTs) to effectively detect active infections is being compromised by the presence of malaria strains with genomic deletions at the hrp2 and hrp3 loci, encoding the antigens most commonly targeted in diagnostics for Plasmodium falciparum detection. The presence of such deletions can be determined in publically available P. falciparum whole genome sequencing (WGS) datasets. A computational approach was developed and validated, termed Gene Coverage Count and Classification (GC3), to analyse genome-wide sequence coverage data and provide informative outputs to assess presence and coverage profile of a target locus in WGS data. GC3 was applied to detect deletions at hrp2 and hrp3 (hrp2/3) and flanking genes in different geographic regions and across time points. METHODS: GC3 uses Python and R scripts to extract locus read coverage metrics from mapped WGS data according to user-defined parameters and generates relevant tables and figures. GC3 was tested using WGS data for laboratory reference strains with known hrp2/3 genotypes, and its results compared to those of a hrp2/3-specific qPCR assay. Samples with at least 25% of coding region positions with zero coverage were classified as having a deletion. Publicly available sequence data was analysed and compared with published deletion frequency estimates. RESULTS: GC3 results matched the expected coverage of known laboratory reference strains. Agreement between GC3 and a hrp2/3-specific qPCR assay reported for 19/19 (100%) hrp2 deletions and 18/19 (94.7%) hrp3 deletions. Among Cambodian (n = 127) and Brazilian (n = 20) WGS datasets, which had not been previously analysed for hrp2/3 deletions, GC3 identified hrp2 deletions in three and four samples, and hrp3 deletions in 10 and 15 samples, respectively. Plots of hrp2/3 coding regions, grouped by year of sample collection, showed a decrease in median standardized coverage among Malawian samples (n = 150) suggesting the importance of a careful, properly controlled follow up to determine if an increase in frequency of deletions has occurred between 2007-2008 and 2014-2015. Among Malian (n = 90) samples, median standardized coverage was lower in 2002 than 2010, indicating widespread deletions present at the gene locus in 2002. CONCLUSIONS: The GC3 tool accurately classified hrp2/3 deletions and provided informative tables and figures to analyse targeted gene coverage. GC3 is an appropriate tool when performing preliminary and exploratory assessment of locus coverage data.

Molecular and morphological identification of frog species collected at Rara Lake in Rara National Park, Nepal.

This study seeks to clarify the taxonomic identity of three adult frogs and two tadpoles from Rara Lake situated in Rara National Park, Mugu district, Western Nepal, using both phenotypic and mitochondrial sequence data (16S rRNA gene). Based on the molecular data, we determined our specimens belonged to two species; Paa cf. ercepeae (Dubois, 1974) and Paa rarica (Dubois, Matsui, and Ohler, 2001), and this assignment is also supported by morphology. Principal component analysis of phenotypic data clustered species into large-bodied (SVL > 55 mm) and small-bodied (SVL < 55 mm) groups. The molecular data suggest that Paa rarica belonged to a group that contains several undescribed lineages and that Paa liebigii (Gnther, 1860) hosts extensive cryptic diversity. Our study also documents that Paa species in the Himalayan region are more widely distributed than previously believed.

A Case of Macrophage Activation Syndrome Manifesting as the Initial Presentation of Systemic Lupus Erythematosus.

Macrophage activation syndrome (MAS) is a potentially fatal complication of an autoimmune rheumatologic disease characterized by overwhelming inflammation, multiorgan failure, and high mortality if untreated. We report a rare case of a 56-year-old man who presented with fever for three weeks and had a constellation of clinical features and laboratory findings, meeting the diagnostic criteria for systemic lupus erythematosus (SLE) and SLE-associated MAS. He was treated with high dose intravenous corticosteroid and hydroxychloroquine, resulting in resolution of fever and dramatic clinical improvement.

National Yearly Trend of Utilization and Procedural Complication of the Watchman Device in the United States.

Background Complication from the Watchman device (Boston Scientific Corp, Marlborough, Massachusetts) is operator-dependent, with the latest EWOLUTION trial showing low complication rates (1.8%) thought to be due to maturing physician experience. Objectives The objective of this study is to understand the yearly trend of utilization and complication rates of the Watchman device in hospitalized patients. Methods The national inpatient sample (NIS) was queried for all hospitalization with primary atrial fibrillation or flutter from 2016 to 2019 with percutaneous left atrial appendage occlusion (LAAO). The frequency of peri-procedural complications, including death, stroke, major bleeding requiring blood transfusion, pericardial effusion, post-op hypotension, cardiac arrest, postprocedural CHF, implant displacement/leak, systemic embolism, and requiring repeat procedures, were assessed. Results From 2016 to 2019, an estimated 60,350 LAAO procedures were performed. The majority of the procedure was done in white (84.88%), males (58.40%), with a mean age of 76, at teaching hospitals (88.27%). Complication rates were around 5.72%, with no change from 2016 to 2019 (annual percentage change, APC: 6.23; p-value: 0.170) despite rapid increase in yearly utilization of Watchman from 1.12% in 2016 to 5.45% in 2019 (APC: 62.30; p-value of 0.013). Pericardial effusion (3.41%) was the most common complication, followed by bleeding requiring transfusion (1.40%) that had no significant change over time. Conclusion Our study demonstrates that trend of complications with the Watchman device implantation in the real-world practice didn't improve over time, possibly due to characteristics inherent to the device and patient population. Hence, we expect a further drop in nationwide complication rates with the improved design of Watchman-FLX and increased placement experience.